Interpretive Summary: Elevated plasma homocysteine (Hcy) is known as an important risk factor for cardiovascular disease. Many studies that investigated the relationship between lifestyle factors, including diet and exercise, often do not agree. We hypothesize that genetic variants modulate the correlation between lifestyle and plasma Hcy. The aim of this study was to investigate the combined effect of genetic and lifestyle factors on plasma Hcy concentrations in a population of Boston Puerto Ricans. We observed that smoking tobacco was significantly associated with plasma levels of Hcy. Persons with a common version of a particular variant had significantly higher plasma Hcy concentrations compared to persons carrying one or two copies of the rarer variant. This was observed in subjects who reported no intake of alcohol. However, persons who had such a variant and reported consumption of alcohol had lower plasma Hcy concentrations. In other words, the combination of carrying a particular genetic variant and consumption of no alcohol associated with increased plasma Hcy, which has been linked to incidence of heart disease. In summary, our results showed that genetic variants modified the effect of lifestyle on plasma Hcy. These findings suggest that healthy lifestyle is particularly important to prevent CVD for a subset of population who carry a particular genetic variant. For instance, to lower Hcy for the prevention of CVD, carriers (66%) of a particular variant would benefit greatly from not smoking, whereas such subjects (34%) may gain benefit from consuming alcohol.